Over the past decade, olefin metathesis has emerged as a powerful carbon-carbon bond-forming reaction that is widely used in organic synthesis and polymer science (Trnka et al., Acc. Chem. Res. 34:18-29 (2001); Fürstner et al., Angew. Chem., Int. Ed. 39:3012-3043 (2000); Ivin et al., J. Mol. Catal. A: Chem. 133:1-16 (1998); Randall et al., J. Mol. Catal. A: Chem. 133:29-40 (1998); and Grubbs et al., Tetrahedron 54:4413-4450 (1998)). “Olefin metathesis,” as is understood in the art, refers to the metal-catalyzed redistribution of carbon-carbon bonds.
A major advance in this field was the development of chiral molybdenum catalysts that exhibit high enantioselectivity in a variety of ring-closing (Alexander et al., J. Am. Chem. Soc. 120:4041-4042 (1998); La et al., J. Am. Chem. Soc. 120:9720-9721 (1998); Cefalo et al., J. Am. Chem. Soc. 123:3139-3140 (2001); and Zhu et al., J. Am. Chem. Soc. 121:8251-8259 (1999)) and ring-opening (La et al., J. Am. Chem. Soc. 121:11603-11604 (1999); and Weatherhead et al., J. Am. Chem. Soc. 122:1828-1829 (2000)) metathesis reactions. See Hoveyda et al., Chem. Eur. J. 7:945-950 (2001) for a general review of molybdenum-catalyzed enantioselective metathesis. However, these molybdenum-based systems require specific substrate-to-catalyst matching, necessitating individual optimization of any one metathesis reaction and the availability of a number of catalysts.
Over two decades of intensive research effort has culminated in the discovery of well-defined ruthenium and osmium carbenes that are highly active olefin metathesis catalysts and stable in the presence of a variety of functional groups.
These ruthenium and osmium carbene complexes have been described in U.S. Pat. Nos. 5,312,940, 5,342,909, 5,831,108, 5,969,170, 6,111,121, and 6,211,391, all to Grubbs et al. The ruthenium and osmium carbene complexes disclosed in these patents all possess metal centers that are formally in the +2 oxidation state, have an electron count of 16, and are penta-coordinated. These catalysts are of the general formula (I):
where M is a Group 8 transition metal such as ruthenium or osmium, X and X′ are anionic ligands, L and L′ are neutral electron donors, and R and R′ are specific substituents, e.g., one may be H and the other may be a substituted or unsubstituted hydrocarbyl group such as phenyl or —C═C(CH3)2. Such complexes have been shown to be useful in catalyzing a variety of olefin metathesis reactions, including ring opening metathesis polymerization (“ROMP”), ring closing metathesis (“RCM”), acyclic diene metathesis polymerization (“ADMET”), ring-opening metathesis (“ROM”), and cross-metathesis (“CM” or “XMET”) reactions. Their broad range of applications is due in large part to their excellent compatibility with various functional groups and relatively high tolerance to moisture, air, and other impurities (Schwab et al., Angew. Chem., Int. Ed. Engl. 34:2039-2041(1995); Schwab et al., J. Am. Chem. Soc. 118:100-110 (1996); Ivin, J. Mol. Cat. A-Chem. 133:1-16 (1998); Grubbs et al., Tetrahedron. 54:4413-4450 (19998); and Randall et al., J. Mol. Cat. A-Chem. 133, 29-40 (1998)). However, as has been recognized by those in the field, the compounds display relatively low thermal stability, decomposing at relatively low temperatures in solution. Jafarpour et al., Organometallics 19(11):2055-2057 (2000). The decomposition is largely limited to solutions of the catalyst as dry (solvent-free) solid catalysts are fairly stable.
For the most part, such metathesis catalysts have been prepared with phosphine ligands, e.g., tricyclohexylphosphine or tricyclopentylphosphine, exemplified by the well-defined, metathesis-active ruthenium alkylidene complexes (II) and (III):
wherein “Cy” is a cycloalkyl group such as cyclohexyl or cyclopentyl. See Grubbs et al., U.S. Pat. No. 5,917,071 and Trnka et al., supra. To increase the reactivity of ruthenium-based catalysts, replacement of one of the phosphine ligands with a 1,3-disubstituted-4,5-dihydro-(4,5-disubstituted)-imidazole-2-ylidene, such as 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene, furnishes more active catalysts, apparently due to a more electron-rich ruthenium metal center (Scholl et al., Tetrahedron Lett. 40:2247-2250 (1999) and Scholl et al., Org. Lett. 1:953-956 (1999)).
From these studies, it became apparent that highly basic N-heterocyclic carbene ligands are an excellent ligand set for improvement in olefin metathesis reactivity, and are superior alternatives to phosphines (Trnka et al., supra; Bourissou et al. Chem. Rev. 100:39-91 (2000); Scholl et al., Tet. Lett. 40:2247-2250 (1999); Scholl et al., Organic Lett. 1(6):953-956 (1999); and Huang et al., J. Am. Chem. Soc. 121:2674-2678 (1999)). N-heterocyclic carbene ligands offer many advantages, including readily tunable steric bulk, vastly increased electron donor character, and compatibility with a variety of metal species. In addition, replacement of one of the phosphine ligands in these complexes significantly improves thermal stability in solution. The vast majority of research on these carbene ligands has focused on their generation and isolation, a feat finally accomplished by Arduengo and coworkers within the last ten years (see, e.g., Arduengo et al., Acc. Chem. Res. 32:913-921 (1999)). Four representative second generation catalysts are the ruthenium complexes (IVA), (IVB), (VA) and (VB):
In the above structures, Cy is as defined previously, Ph represents phenyl, “IMes” represents 1,3-dimesityl-imidazol-2-ylidene:
and “IMesH2” represents 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene:
Other ruthenium-based olefin metathesis catalysts formed with N-heterocyclic carbene ligands are known.
These transition metal carbene complexes, particularly those containing a ligand having the 4,5-dihydroimidazol-2-ylidene structure such as in IMesH2, have been found to address a number of previously unsolved problems in olefin metathesis reactions, particularly cross-metathesis reactions. However, in all previous applications of Group 8-catalyzed olefin metathesis, such as ring-closing metathesis, there has been no general method for controlling the enantioselectivity of the catalytic process. Additionally, the molybdenum-based catalysts are limited since these systems lack extensive functional group tolerance and require rigorous exclusion of air and moisture.
Therefore, there is a need for the development of enantioselective metathesis catalysts based on Group 8 transition metals such as ruthenium. The instant invention addresses this need by providing for various novel chiral 1,3-disubstituted-4,5-dihydro-(4,5-disubstituted)-imidazol-2-ylidene ligands and analogs thereof, methods for their synthesis, as well as methods of use in the synthesis of novel chiral Group 8 transition metal complexes useful as olefin metathesis catalysts. The chiral N-heterocyclic carbene (NHC) ruthenium complexes of the invention exhibit high enantioselectivity, for example up to 90% ee in the ring-closing metathesis of achiral trienes. While chiral N-heterocyclic carbene ruthenium complexes have been reported previously (Scholl et al., Org. Lett. 1:953-956 (1999) and Weskamp et al., Angew. Chem. Int. Ed. 37:2490-2493 (1998)), none report their use in asymmetric metathesis.